RESUMO
Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, C(max) and AUC(last) parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Desenho de Fármacos , Imidazóis/química , Imidazóis/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Tetrazóis/química , Tetrazóis/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Animais , Área Sob a Curva , Cromatografia Líquida , Avaliação Pré-Clínica de Medicamentos , Ésteres , Suco Gástrico/metabolismo , Meia-Vida , Imidazóis/síntese química , Espectroscopia de Ressonância Magnética , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Pró-Fármacos/síntese química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Tetrazóis/síntese químicaRESUMO
Synthesis of a new series of diarylureas and diarylamides having 1H-pyrrolo[3,2-c]pyridine scaffold is described. Their in vitro antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on pyrrolo[3,2-c]pyridine nucleus was investigated. The newly synthesized compounds, except three N-tolyl derivatives (8f, 9f, and 9h), generally showed superior activity against A375P to Sorafenib. Among all of these derivatives, compounds 8b, 8g, and 9a-e showed the highest potency against A375P with IC(50) in nanomolar range. In addition, compounds 8d, 8e, 8h, 9g, 9i, and 9j were more potent than Sorafenib but with IC(50) in micromolar range. Compounds 8b, 8g, 9b-d, and 9i demonstrated higher selectivity towards A375P compared with NIH3T3 fibroblasts. The most potent diarylurea 8g and diarylamide 9d were further tested and showed high potency over nine melanoma cell lines at the NCI.
Assuntos
Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Melanoma/patologia , Piridinas/síntese química , Pirróis/síntese química , Neoplasias Cutâneas/patologia , Animais , Antineoplásicos/farmacologia , Benzenossulfonatos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Melanoma/tratamento farmacológico , Camundongos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/farmacologia , Pirróis/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Sorafenibe , Relação Estrutura-AtividadeRESUMO
Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30 min. The pharmacokinetic parameters of IIa were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a promising prodrug of olmesartan.
